Characterizing Toll-like Receptor 4 Activation by Filoviruses for Development of Novel Therapeutics

The COVID-19 pandemic highlighted the threat posed by emerging viruses, and more are poised to emerge. Filoviruses, a group of viruses including Ebola virus (EBOV), have pandemic potential and cause deadly outbreaks with mortality rates of up to 90%. Outbreaks are occurring with increasing frequency as the geographical range of bats carrying these viruses expands. Not all filoviruses are deadly in humans, but we are not sure why this is, nor do we understand how bats harbour these and other viruses without experiencing disease. Toll-like receptor 4 (TLR4), a receptor expressed on immune cells, is thought to influence the severity of EBOV disease. A specific EBOV component called the glycoprotein activates TLR4, which can cause excessive inflammation, leading to death. SARS-CoV-2 spike and other viral glycoproteins of emerging viruses also activate TLR4, although how this occurs is poorly understood. I will investigate how TLR4 activation is influenced by differences in filovirus glycoproteins, genetic variation in human TLR4, and genetic differences in TLR4 between bats and humans. I will compare glycoproteins of filoviruses that do and do not cause disease in humans to study virus glycoprotein-related factors affecting TLR4 activation. I will investigate how genetic differences in TLR4 present in the human population impact responses to filovirus glycoproteins. Finally, I will compare bat and human TLR4 activation to help understand how bats harbour viruses without becoming ill. Studying the interaction of filovirus glycoproteins with TLR4 will inform a model for assessing the risk of other novel viruses with pandemic potential, enabling appropriate responses to help prevent pandemics. We can better treat viral disease with personalized medicine if we know why some individuals experience more severe disease. Understanding what makes bats resistant to viral disease will inform new treatment approaches to prepare us for future viral outbreaks and pandemics.